tbuckley/cabot-search huggingface dataset:
Screening the key pathogenic mutations in Chinese patients with colorectal cancers using liquid and tissue biopsy.
Authors: He Wu, Huixin Peng
Journal: Journal of Clinical Oncology (2023)

e15637 Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Over the past decades, significant progress has been made in the clinical treatment of CRC. Targeted therapy is an optional approach that has successfully prolonged overall survival for CRC patients. It is necessary to determine the personalized targets for guiding the usage of specific drugs, which requires biopsy to obtain pathological samples for analysis. Both tissue biopsy and liquid biopsy are commonly used in clinical diagnosis, while each has its own advantages and limitations. The mutation detection rate of tissue biopsy is usually higher, and more genes can be detected, but most tissue biopsies require surgery to obtain samples and may be biased due to the intra-tumor heterogeneity. Liquid biopsy is less harmful to patients, but the detection sensitivity is much lower than tissue biopsy. Methods: In this study, 353 paraffin tissue section samples were used as tissue biopsy samples and 112 blood samples were used as liquid biopsy samples. All samples are from Chinese patients and are collected from December 2021 to August 2022. Whole-genome sequencing was performed, and several processes have been conducted to eliminate noise, duplicates and reads with low depth, therefore the gene mutations detected in the samples were considerably reliable. We selected APC, TP53, KRAS, PIK3CA and BRAF as the key pathogenic genes for CRC, analyzed the mutation detection results in tissue and blood samples. The detection difference between two types of biopsies was assessed using Pearson's Chi-squared test. Results: Among all samples, 21 (5.95%) tissue biopsy samples and 37 (33.04%) liquid biopsy samples did not contain any key pathogenic genes. For all biopsy samples, the detection rates for APC in tissue biopsy samples (n = 236, 66.86%) and liquid biopsy samples (n = 49, 43.75%) demonstrate significant difference (p = 2.02e-05). The differential detection rates were also observed in TP53 (n = 223 vs. n = 51, 63.17% vs. 45.54%, p = 0.0014) and KRAS (n = 183 vs. n = 39, 51.84% vs. 34.82%, p = 0.0024). There is no significant difference in detection rates of PIK3CA (n = 77 vs. n = 15, 21.81% vs. 13.39%, p = 0.0699) and BRAF. Only 25 (7.08%) tissue biopsy samples and 8 (7.14%) liquid biopsy samples were found to detect BRAF (p = 1). Conclusions: Generally, there is no doubt that the overall detection sensitivity of tissue biopsy is higher than that of liquid biopsy for CRC, and our analysis provided the statistical support. But for some relatively rare disease-causing genes, there is not much difference between the two biopsy methods. For patients, tissue biopsies can be more painful than liquid biopsies, so how to improve the detection of liquid biopsy in CRC is still a subject that requires efforts.
The FOxTROT platform: Clinical trials and exploratory research for personalization of neoadjuvant (NA) therapy in locally advanced colon cancer (LACC)—ISRCTN83842641.
Authors: Christopher Williams, Mark White, James Robert Platt, James Glasbey, Lucy Bailey, Laura Magill, Peter Wheatstone, Libby Cooper, Andrew David Beggs, Michael Braun, David A. Cairns, Alexandra Gilbert, Damian Tolan, Nicholas West, Janet Shirley Graham, Dion Morton, Jenny F. Seligmann
Journal: Journal of Clinical Oncology (2023)

TPS3636 Background: The FOxTROT1 trial demonstrated a significant reduction in 2-year (yr) recurrence with 6 weeks (wks) of oxaliplatin and fluoropyrimidine (OxFp) NA chemotherapy (NAC) in patients (pts) with LACC, establishing NAC as a new therapeutic option. The ongoing FOxTROT platform will refine and personalize NA therapy in LACC. FOxTROT2 is testing NAC in older pts and those with frailty, who are poorly represented in clinical trials. FOxTROT3 is assessing intensified NAC with modified FOLFOXIRI (mFOLFOXIRI; 5-fluorouracil, oxaliplatin, irinotecan) in fit pts. The FOxTROT platform will also test targeted treatments with established safety and efficacy in defined molecular subgroups. FOxTROT4 is investigating the efficacy and safety of NA encorafenib and cetuximab in BRAF-mutant pMMR LACC. Other arms in setup are shown in Table. Methods: FOxTROT platform trials are international, multicenter, open-label, phase II/III RCTs. Pts with resectable, cT3-4 N0-2 M0, biopsy-proven colon adenocarcinoma are eligible for recruitment. Pts whose age or frailty precludes mFOLFOXIRI can be considered for FOxTROT2. Pts suitable for mFOLFOXIRI can be considered for FOxTROT3. BRAF-mutant pMMR pts can be considered for FOxTROT4. Pts are randomized 2:1 between intervention and control arms. FOxTROT2 randomizes between 6 wks OxFp NAC (choice of 100% or 80% dose) vs proceeding straight to surgery. Adjuvant chemotherapy (AC) is per physician choice. Primary outcome is 3-yr DFS. 759 pts will be recruited over 5 yrs. FOxTROT3: 6 wks mFOLFOXIRI NAC vs 6 wks OxFp NAC. All pts receive AC but physicians may de-escalate mFOLFOXIRI to OxFp. Hierarchical co-primary endpoints: tumor regression grade (TRG) (blinded central assessment) and 3-yr DFS. 873 pts over 5 yrs. FOxTROT4: 6 wks NA encorafenib and cetuximab vs 6 wks OxFp NAC. AC is per physician choice. Primary outcome: TRG. 45 pts over 3 yrs. Secondary outcomes include: histopathological endpoints, downstaging, minimal residual disease by ctDNA, safety, toxicity, OS, surgical outcomes and patient-reported outcomes; and DFS in FOxTROT4. The FOxTROT platform opened 7 th Feb 2022, funded by Yorkshire Cancer Research. At submission, 50 pts had been randomized at 23 centers. Trial design and management is conducted in partnership with patient representatives. A program of translational and radiomics research is running in parallel. International recruitment in France and India will commence in 2023 with additional international partners joining from 2024. Clinical trial information: ISRCTN83842641 . [Table: see text]
Edema and serositis as an adverse event in patients with cancer receiving immune checkpoint blockade: Systematic review to evaluate this immune-related adverse event and associated treatment strategies.
Authors: Evelyn Elias, Nicholas Cole Rohs, Mako Koseki, Fnu Chesta, Kensuke Takaoka, Yoshito Nishimura, Yu Fujiwara
Journal: Journal of Clinical Oncology (2023)

2649 Background: Immune checkpoint blockade (ICB) is a standard therapeutic option for certain patients with solid tumors, often leading to durable responses. Immune-related adverse events (irAEs) can impact treatment duration and patients' quality of life. The mechanism of irAEs is proposed to be an inflammatory response triggered by blocking immune checkpoints, and nonspecific symptoms like edema and fluid accumulation can occur. We performed a systematic review to summarize reported studies evaluating edema and serositis to explore edema and serositis as an irAE and management strategies. Methods: We performed a database search in Medline, Embase, and Web of Science for studies reporting the incidence and outcome of immune-related generalized edema (irGE) including peripheral edema, capillary leak syndrome, serositis, pleural/peritoneal/pericardial effusion, and anasarca as an irAE among patients with solid tumors treated with ICB. Two independent reviewers analyzed the eligibility of each article. Those that did not report outcomes related to irGE were excluded. The number of patients, cancer type, name and type of ICB, type of irGE, treatment of irGE, and treatment outcome for irGE were extracted from each article to summarize the characteristics of irGE. Results: 662 articles were identified, and 80 studies were included (65 case reports/series, 8 cohort studies, 3 phase 1/2 clinical trials) that described clinical characteristics and treatment outcomes for AEs from 196 patients, and 259 irGE incidences reported. The median age was 62 (Interquartile range: 55-68). 35.9% of cases were female (n=28/78). Commonly reported irGEs were pericardial effusion (n=115, 44.4%), pleural effusion (n=58, 22.4%), peripheral edema (n=40, 15.4%), and ascites (n=19, 7.3%). PD-1 blockade was utilized in 75.8% of cases, followed by PD-L1 blockade (14.9%) and dual ICB (CTLA4 and PD-1 blockade, 4.6%). Common cancers where irGE occurred were: lung cancer (63.9%), malignant melanoma (17.0%), and urothelial carcinoma (3.1%). We classified irGEs into primary irGE (n=84, 42.9%), secondary to other irAEs (n=41, 20.9%), secondary to pseudoprogression (n=14, 7.1%), and cancer progression (n=13, 6.6%). Glucocorticoid was used to manage irGEs in 91 patients (46.4%); 48 cases (24.5%) required the prednisone-equivalent dose of &gt; 1 mg/kg/day. ICB discontinuation was confirmed in 96 cases (49.0%) among which 53 (27.0%) permanently stopped ICB use due to irGEs. Conclusions: irGE is an important irAE among patients with solid tumors receiving ICB. Most cases required glucocorticoid therapy along with discontinuation of ICB, which could result in poorer quality of life and potentially impact outcomes. The pathophysiology, incidence and clinical outcomes of irGE need to be accurately described in further studies.
Expression profiles of MUC5AC glycoforms in neoplastic and non-neoplastic pancreatic tissue.
Authors: Ashish Manne, Xiang Cheng, Allan Tsung, Ashwini K Esnakula
Journal: Journal of Clinical Oncology (2023)

e16008 Background: MUC5AC, secretory mucin, exists in two major glycoforms, heavily-glycosylated mature (MM) and less-glycosylated immature (IM) isoforms. Prior IM-based tissue expression studies could not establish the clinical significance of MUC5AC in pancreatic ductal adenocarcinoma (PDA). Despite having strong pre-clinical evidence of MM’s role in local invasion, metastasis, and drug (gemcitabine) resistance, its impact on PDA outcomes is unclear. In this study, for the first time, we examined the differential expression of MM and IM by immunohistochemistry in primary PDA (pPDA), metastatic PDA (mPDA), normal pancreatic tissue adjacent to tumor (NAJ), neuroendocrine tumors (NET), Pancreatitis (P), normal pancreas (N) using tissue microarrays (TMA). Methods: Commercially available TMA (PA2081c, tissuearray.com, Derwood, MD) constructed from 96 patients, including 38 pPDA (14-stage 1, 22-Stage 2, and 2-stage 3), 5 mPDA, 24 NAJ, 11 NET, 8 P and 10 N was used in this study. Two separate 1 mm cores represented each case. Immunohistochemistry for MUC5AC was performed using CHL2 clone (ab77576, abcam, Boston, MA) for the IM isoform and 45M1 clone (ab369, abcam, Boston, MA) for the MM isoform. The immunostains were optimized as per the manufacturer's recommendations using appropriate controls. The sections are evaluated for the intensity of expression (0-3) and the percentage of reactive cells, and an H-score is derived from the product of these measurements. Cases are categorized as having negative/weak (score &lt;10) or positive (score &gt;10) expression. For every positive case, the pattern of expression in terms of Apical (Ap), cytoplasmic (Cy), and extracellular (EC) expression was recorded. Results: MUC5AC (MM and IM) is not expressed in N, NAJ, and P. MM expression is only noted in 44% of PDAs (19/43; 18 pPDA and 1 omental mPDA lesion). Three different expression patterns were noted, including Ap (63%), Cy (84%), and EC (47%). IM expression was detected in 60% of PDAs (26/43, 25 pPDA and omental mPDA lesion) and 18% NET (2/11). IM expression was noted in cases with EC MM expression (9/43, 21%), suggesting that IM was further glycosylated to MM and expressed extracellularly in some patients. MM and MM were co-expressed in 40% of PDA (17/43). Liver and abdomen metastatic lesions in the TMA did not express IM or MM. Pertinent clinical information was not available to study the impact of MM’s expression on PDA outcomes. Conclusions: Our study shows that MUC5AC is primarily expressed in PDAs and can be a useful biomarker. Larger studies are ongoing to correlate tissue expression patterns in PDAs for evidence of any association with early recurrence or treatment failure. Preliminary data suggests that only MM isoform is expressed extracellularly and could be detected in patient serum and serve as a potential non-invasive biomarker for treatment selection (for gemcitabine resistance) and monitor the response in certain cases.
Clinical efficacy analysis of patients (pts) with HER-2 expressing metastatic urothelial carcinoma (mUC) treated with enfortumab vedotin (EV).
Authors: Cindy Jiang, Omar Alhalabi, Jaime Haro-Silerio, Wei Qiao, Amishi Yogesh Shah, Arlene O. Siefker-Radtke, Jianjun Gao, Sangeeta Goswami, Ajjai Shivaram Alva, Vadim S. Koshkin, Charles Guo, Matthew T. Campbell
Journal: Journal of Clinical Oncology (2023)

e16618 Background: EV, an antibody drug conjugate (ADC) targeting NECTIN-4, is an approved salvage treatment for unselected pts with mUC. ADCs targeting the human epidermal growth factor receptor-2 (HER-2) have also shown robust activity in clinical trials for mUC with tumor HER-2 expression. We investigated the interaction between HER-2 expression and clinical outcomes of pts treated with EV, which are currently unknown. Methods: We conducted a retrospective, single institution study analyzing pts with mUC who received EV. Immunohistochemistry (IHC) staining for HER-2 was completed with PATHWAY anti-HER2 (4B5) Antibody (Ventana Medical Systems, Tucson, AZ) using established breast cancer scoring algorithm. Wilcoxon rank sum and Fisher exact tests were used to compare continuous and categorical variables, respectively. Cox proportional hazards regression model was used to evaluate a variable’s ability to predict overall survival (OS). Variables with p-value ≤0.1 were included in the multivariate analysis (MVA). Results: We identified 158 pts with mUC who received EV. Median age at EV start was 70 (IQR 66-76), most pts were Caucasian (144, 91%), male (108, 68%), primary bladder tumors (113, 72%), and pure urothelial histology (95, 60%). 96 pts (61%) received prior platinum therapy and 117 pts (74%) had prior immunotherapy. ECOG scores ≥2 was seen in 54 pts (39%) while 75 pts (54%) had Bellmunt scores ≥2 (54%). Median follow up time was 12.5 months and median OS from EV start was 13 months. 94 pts (60%) had HER2 IHC staining. There was no association between HER2 intensity and any of the clinical variables. On univariate analysis (UVA): HER2 3 vs HER2 ≤2 HR was 0.38 (0.14, 0.98), male vs female HR=1.56 (0.94, 2.58), ECOG ≤1 vs ≥2 HR=0.6 (0.38,0.95), Bellmunt score 0-1 vs 2-3 HR=0.49 (0.3, 0.78), and hemoglobin (Hgb) HR=0.75 (0.67, 0.85). MVA showed HER2 3 vs HER2 ≤2 HR was 0.42 (0.16, 1.12), male vs female HR=2.3 (1.17, 4.42), ECOG ≤1 vs ≥2 HR=0.56 (0.30, 1.05), and Hgb HR=0.77 (0.65, 0.92). Conclusions: MVA of this single-site retrospective cohort did not show any association between HER2 expression and survival outcomes in pts with mUC who received EV. Further studies are needed to continue assessing the role of HER2 as a potential prognostic and predictive biomarker in UC, especially if HER-2 directed therapies become incorporated in the mUC treatment paradigm. [Table: see text]
Predicting the risk of pancreatic cancer in patients with new-onset diabetes based on CT image.
Authors: Yu Zhou, Jiabin Yang, Liangtang Zeng, Lei Wu, Zhuo Wu, Si-Yang Liu, Shangyou Zheng, Changhao Chen, Rufu Chen
Journal: Journal of Clinical Oncology (2023)

e16320 Background: While long-standing diabetes mellitus (LsDM) is an etiologic factor for PC, new-onset diabetes (NoDM) has been considered as a manifestation and harbinger of this cancer as well. Current evidence support that the PC-associated NoDM was mainly caused by disease of the exocrine pancreas, which was different from the typical type 2 DM. Therefore, we hypothesize that, in the NoDM patients, CT image features of “normal” pancreas from PC-associated NoDM patients might be different from that of the new-onset type 2 DM. We sought to develop and validate a risk prediction model to facilitate the distinction between NoDM vs potential early PC-associated NoDM on pancreatic CT imaging. Methods: We retrospectively collected CT imaging from three types of patients at Guangdong Provincial People's Hospital between January 2015 and December 2022: PC patients with pathological diagnosis of pancreatic ductal adenocarcinoma (n=249: 139 patients without DM, 63 patients with NoDM, 47 patients with LsDM), NoDM patients diagnosed with PC within 3 years (n=12), NoDM patients without development of cancer within the next 5 years (n=151). We used four different machine learning algorithms, including support vector machine (SVM), random forest (RF), eXtreme Gradient Boosting (XGB), and generalized linear model (GLM), and gradient boost methods, to build prediction models based on PC pateints and cancer-free NoDM patients. The algorithm with best ROC was used to build a final model, which was validated in the “normal” CT images of NoDM patients prior to their diagnosis of PC within 3 years. Results: In PC cases, the radiomics features exclusive to NoDM-PC cases were selected using a non-parametric test, and 134 radiomics features were retained (86 from arterial and 48 from venous phases, respectively). The RF algorithm showed best prediction skill (AUC of ROC: 0.952). Based on the variable importance measures in the RF algorithm, a risk-scoring model was generated for NoDM patients as a tool to differentiate between PC patients and cancer-free DM patients. As a result of validation, the scores calculated based on the “normal” CT images of NoDM patients prior to their diagnosis of PC within 3 years, were significantly higher than the scores from CT images of NoDM patients who were cancer-free within the next 5 years (P &lt; 0.01). Conclusions: In NoDM patients, even the PC lesion was nonvisible on CT, the radiomics features of “normal” pancreas of PC patients were different from that of the real DM patients. Our model has the potential for identifying individuals with PC in the whole NoDM population.
CCTG EN10: A phase II study of tailored adjuvant therapy in <i>POLE</i>-mutated and p53-wildtype/NSMP early-stage endometrial cancer (EC)—RAINBO BLUE and TAPER.
Authors: Jessica N. McAlpine, Kathy Chai-Zung Han, Mary Kinloch, Maroie Barkati, Sarah E. Ferguson, Anthony W. Fyles, Fleur Huang, Iwa Kong, Janice S. Kwon, Helen Mackay, Mark Stafford Carey, Stephen Welch, Tjalling Bosse, Carien L. Creutzberg, Nanda Horeweg, Alexandra Leary, WenLing Liu, Dongsheng Tu, Wendy R. Parulekar
Journal: Journal of Clinical Oncology (2023)

TPS5632 Background: Molecular classification of EC provides an opportunity to personalize treatment for patients with early disease based on prognosis. We hypothesize that de-escalated adjuvant treatment in patients with early-stage POLE-mutated ( POLEmut) or p53wt/NSMP (p53 wildtype/no specific molecular profile) EC is feasible and associated with favourable disease control, QOL and health economics. Methods: EN.10 is a Canadian Cancer Trials Group led phase II trial that enrolls two independent cohorts of patients with early stage EC based on tumour molecular status: POLEmut (substudy A) and p53wt/NSMP (substudy B). The primary objective is to estimate the 3-year rate of pelvic recurrence. Secondary objectives include estimated 3-year isolated vaginal recurrence, para-aortic recurrence, distant metastasis, survival (recurrence-free, EC-specific, overall survival) and to describe the patient decisional conflict and fear of recurrence. Tertiary objectives: QOL, economic evaluation and interrogation/discovery of additional prognostic biomarkers. Statistical Design: Registration to Substudy A or B is based on molecular classification. Treatment will be deescalated in both substudies; to surveillance-only (all early stage POLEmut, and a proportion of NSMP), or vaginal brachytherapy (proportion of NSMP), with NSMP stratification based on histological grade, and lymphovascular invasion. Substudy A can enroll endometrioid, serous, clear cell, un/dedifferentiated and carcinosarcomas whereas Substudy B is confined to endometrioid histotype. Both arms require ECOG 0-2 and hysterectomy+BSO with nodal assessment required for stage II and grade 3 EC. A total of 120 patients with POLEmut (Sub-study A) and 180 with p53wt/NSMP ER+ (Sub-study B) EC will be recruited in 3 years. If the upper 95% confidence limit is less than 5% in either of Substudy A, Cohort A1 and Sub-study B or both, it will be concluded that patients in one or both groups have an acceptable low risk of pelvic recurrence at 3 years with molecularly-tailored de-escalated adjuvant treatment An additional estimated 25 patients with higher risk POLEmut EC will be enrolled for an exploratory analysis. Conduct to Date: Study activation Dec 19 2022. Enrollment January 31, 2023: 36 Supported by Canadian Cancer Society, Canadian Institutes of Health Research, Gynecologic Cancer Initiative, BC Cancer Foundation. Clinical trial information: NCT05640999 .
Effect of TFF2-MSA on tumor growth and survival in anti-PD-1 treated MC38 and CT26.wt colorectal cancer models by targeting MDSCs.
Authors: Bruce L Daugherty, Rebecca J Boohaker, Rebecca Johnstone, Karr Stinson, Jin Qian, Timothy C. Wang, Seth M. Lederman
Journal: Journal of Clinical Oncology (2023)

e15654 Background: Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are potential therapeutic targets in immune checkpoint cancer therapy, particularly for cancers that are unresponsive to anti-PD-1 therapy. It has previously been demonstrated that trefoil factor family 2 (TFF2), a secreted anti-inflammatory peptide, can partially suppress MDSC expansion and partially activate tumor immunity through agonism of the CXCR4 receptor. We investigated whether a novel fusion protein, TFF2-murine serum albumin (TFF2-MSA), has single agent activity and can improve on the therapeutic effects of anti-PD-1 in the MC38 and CT26.wt syngeneic mouse models of advanced colorectal cancer (CRC). Methods: Two syngeneic colon carcinoma mouse models were developed using the MC38 and CT26.wt CRC cell lines grafted subcutaneously into C57BL/6 and BALB/C mice, respectively. We generated a recombinant fusion protein, designated TFF2-MSA, which contains murine TFF2 fused to murine serum albumin (MSA), for the purpose of increasing half-life and reducing the frequency of dosing. Mice subsequently received TFF2-MSA, anti-PD-1 antibody (clone 29F.1A12) or combination TFF2-MSA/anti-PD-1. Tumor volume, and survival were measured. At the endpoint, flow cytometry was performed on the draining and axillary lymph nodes, to examine treatment-induced effects on cellular immune profiles. Results: In the MC38 model, on Day 49 of treatment, tumor growth was suppressed (TGI) by TFF2-MSA alone, anti-PD-1 alone, and by combination TFF2-MSA/anti-PD-1 by 50%, 82% and 87% TGI, respectively. The survival rates at 50 days of mice treated with vehicle, TFF2-MSA, anti-PD-1, or combination TFF2-MSA/anti-PD-1 were 20%, 50% and 80%, and 90%, respectively. In the combination TFF2-MSA/anti-PD-1 treated mice, 40% demonstrated a complete response. In the CT26.wt model, tumor growth was suppressed by TFF2-MSA, anti-PD-1 and by combination TFF2-MSA/anti-PD-1 by 17%, 43% and 67%, respectively. Survival in the CT26.wt model at Day 30 treated with vehicle, TFF2-MSA, anti-PD1 and the combination of TFF2-MSA/anti-PD-1 was 0%, 40%, 60% and 60%, respectively. The percentage of exhausted CD8+ T cells was markedly reduced in the draining lymph node by the combination TFF2-MSA/anti-PD-1 treatment, as measured by flow cytometry using antibodies against LAG3, TIM3, and PD-1. Conclusions: TFF2-MSA has single agent activity and is additive to anti-PD-1 antibody checkpoint inhibition in treating syngeneic mouse models of advanced CRC. In a separate abstract, additive effects between TFF2-MSA and anti-PD-1 antibody were also demonstrated in a separate ACKP (Atp4b-Cre; Cdh1-/-; LSL-KrasG12D; Trp53-/-) gastric cancer model, suggesting combination therapy may also be applicable to gastric cancer.